更新于：2024-11-01

H3 receptor

更新于：2024-11-01

基本信息

别名

组胺H3受体、G-protein coupled receptor 97、GPCR97

+ [5]

简介

The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system. Signals through the inhibition of adenylate cyclase and displays high constitutive activity (spontaneous activity in the absence of agonist). Agonist stimulation of isoform 3 neither modified adenylate cyclase activity nor induced intracellular calcium mobilization.

关联

103

项与 H3 receptor 相关的药物

Pitolisant Hydrochloride

盐酸替洛利生

靶点

H3 receptor

作用机制

H3 receptor拮抗剂

在研机构

Bioprojet Pharma SARL [+5]

原研机构

Bioprojet Pharma SARL

在研适应症

白天过度嗜睡 [+6]

非在研适应症

酒精使用障碍 [+6]

最高研发阶段批准上市

首次获批国家/地区

欧盟 [+3]

首次获批日期2016-03-31

Betahistine Hydrochloride

盐酸倍他司汀

靶点

H1 receptor x H3 receptor

作用机制

H1 receptor拮抗剂 [+1]

在研机构

Altamira Therapeutics Ltd. [+1]

原研机构-

在研适应症

动脉硬化 [+4]

非在研适应症

高胆固醇血症 [+3]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期1966-01-01

ALTO-203

靶点

H3 receptor

作用机制

H3 receptor激动剂

在研机构

Alto Neuroscience, Inc.初创企业

原研机构

Alto Neuroscience, Inc.初创企业

在研适应症

快感缺乏 [+3]

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

250

项与 H3 receptor 相关的临床试验

CTIS2024-513383-26-00 / Recruiting

- P24-03

开始日期2024-10-01

申办/合作机构

Bioprojet Pharma SARL

NCT06503510 / Not yet recruitingN/AIIT

The Role of the Interleukin-13 Pathways on Pain and Itch Sensitivity in Patients With Atopic Dermatitis and Healthy Volunteers

Atopic dermatitis (AD) is as chronic, inflammatory skin disorder affecting 20% of the world's population. Intense itch and skin pain are the main symptoms. Research has shown that the proteins interleukins are involved in inflammation and itch in atopic dermatitis. The medicinal product called Lebrikizumab, used for treatment of AD, has shown to block the interleukin called IL-13. The purpose of this experiment is to evaluate the role of IL-13 in itch in both healthy subjects and people with atopic dermatitis.

开始日期2024-10-01

申办/合作机构

University of Aalborg

NCT06503523 / Not yet recruitingN/AIIT

Investigation of the Neurophysiological and Psychological Aspects of Itch

The aim of this project is to determine the effects of performing a motor imagery task on cortical excitability during acute experimental muscle pain (induced by hypertonic saline), acute histaminergic itch (induced by histamine), and non-histaminergic itch stimulation (triggered by Cowhage). We hypothesize that motor imagery will counteract the alterations in cortical excitability observed during experimental muscle pain and both itch models.

开始日期2024-09-01

申办/合作机构

University of Aalborg

100 项与 H3 receptor 相关的临床结果

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100 项与 H3 receptor 相关的转化医学

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0 项与 H3 receptor 相关的专利（医药）

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1,289

项与 H3 receptor 相关的文献（医药）

2024-11-01·Neuroscience

Histamine H3 receptor activation in the insular cortex during taste memory conditioning decreases appetitive response but accelerates aversive memory extinction under an ad libitum liquid regimen

Article

作者: Alcalá, Alejandra ; Miranda, María-Isabel

Conditioned taste aversion (CTA) is a robust associative learning; liquid deprivation during this conditioning allows researchers to obtain readable measures of associative learning. Recent research suggests that thirst could be a crucial motivator that modulates conditioning and memory extinction processes, highlighting the importance of the body's internal state during learning. Furthermore, the histaminergic system is one of the major modulatory systems controlling several behavioral and neurobiological functions, such as feeding, water intake, and nociception. Therefore, this research aimed to assess the effect of H3 histaminergic receptor activation in the insular cortex (IC) during CTA. For this, we conditioned adult male Wistar rats under two regimens: water deprivation and water ad libitum. A classical CTA protocol was used for water deprivation. Before CTA acquisition, 10 μM R-α-methylhistamine (RAMH), an H3 receptor agonist, was injected into the IC. Results showed that RAMH injections decreased CTA in water-deprived rats without affecting the significant aversion conditioning in rats that were given water ad libitum. Moreover, RAMH accelerated the process of aversive memory extinction under ad libitum water conditions. According to our findings, the degree of liquid satiety differentially affected taste-aversive memory formation, and H3 histamine receptors were more involved under water deprivation conditions during acquisition. However, these receptors modulated the strength of aversive conditioning by altering the rate of aversive memory extinction in the absence of deprivation. In conclusion, histaminergic activity in the IC may influence taste memory dynamics through different mechanisms depending on the degree of liquid satiety or deprivation during conditioning.

2024-10-01·Biochemical Pharmacology

Ligand-directed biased agonism at human histamine H3 receptor isoforms across Gαi/o- and β-arrestin2-mediated pathways

Article

作者: Rahman, Sabrina N ; Langmead, Christopher J ; Imhaouran, Faissal ; Valant, Céline ; Leurs, Rob ; Christopoulos, Arthur

The histamine H₃ receptor (H₃R) is a neurotransmitter receptor that is primarily found in the brain, where it controls the release and synthesis of histamine, as well as the release of other neurotransmitters (e.g. dopamine, serotonin). Notably, 20 H₃R isoforms are differentially expressed in the human brain as a consequence of alternative gene splicing. The hH₃R-445, -415, -365 and -329 isoforms contain the prototypical GPCR (7TM) structure, yet exhibit deletions in the third intracellular loop, a structural domain that is pivotal for G protein-coupling, signaling and regulation. To date, the physiological relevance underlying the individual and combinatorial function of hH₃R isoforms remains poorly understood. Nevertheless, given their significant implication in physiological processes (e.g. cognition, homeostasis) and neurological disorders (e.g. Alzheimer's and Parkinson's disease, schizophrenia), widespread targeting of hH₃R isoforms by drugs may lead to on-target side effects in brain regions that are unaffected by disease. To this end, isoform- and/or pathway-selective targeting of hH₃R isoforms by biased agonists could be of therapeutic relevance for the development of region- and disease-specific drugs. Hence, we have evaluated ligand biased signaling at the hH₃R-445, -415, -365 and -329 isoforms across various Gα_i/o-mediated (i.e. [³⁵S]GTPγS accumulation, cAMP inhibition, pERK1/2 activation, pAKT T308/S473 activation) and non Gα_i/o-mediated (i.e. β-arrestin2 recruitment) endpoints that are relevant to neurological diseases. Our findings indicate that H₃R agonists display significantly altered patterns in their degree of ligand bias, in a pathway- and isoform-dependent manner, underlining the significance to investigate GPCRs with multiple isoforms to improve development of selective drugs. SUBJECT CATEGORY: Neuropharmacology.

2024-10-01·Bioorganic Chemistry

Scutellarein derivatives with histamine H3 receptor antagonism and cholinesterase inhibitory potency as multi target-directed ligands for possible Alzheimer’s disease therapy

Article

作者: He, Zhu ; Tang, Lei ; Zhao, Yonglong ; Li, Li ; Wang, Yujie ; Li, Yongjun ; Yang, Shenggang ; Chen, Jiao ; Dai, Zeqin ; Liu, Ting ; Fu, Xiaozhong ; Luo, Qianhen ; Luo, Keke

A series of scutellarein 7-_l-amino acid carbamate-4'-cycloalkylamine propyl ether conjugates were designed and synthesized for the first time as multifunctional agents for Alzheimer's disease (AD) therapy. The designed compounds exhibited more balanced and effective multi-target potency. Among them, compound 11l, _l-Valine carbamate derivative of scutellarein cycloheptylamine ether, exhibited the most potent inhibition of electric eel AChE enzymes and human AChE enzymes, with an IC₅₀ values of 7.04 μM and 9.73 μM, respectively. Moreover, 11l exhibited more potent H₃R antagonistic activities than clobenpropit, with an IC₅₀ value of 1.09 nM. Compound 11l not only displayed excellent inhibition of self- and Cu²⁺-induced Aβ_1-42 aggregation (95.48 % and 88.63 % inhibition, respectively) but also induced the disassembly of self- and Cu²⁺-induced Aβ fibrils (80.16 % and 89.30 % disaggregation, respectively). Moreover, 11l significantly reduced tau protein hyperphosphorylation induced by Aβ_25-35. It exhibited effective antioxidant activity and neuroprotective potency, and inhibited RSL3-induced PC12 cell ferroptosis. Assays of hCMEC/D3 and hPepT1-MDCK cell line permeability indicated that 11l would have optimal blood-brain barrier permeability and intestinal absorption characteristics. In addition, in vivo studies revealed that compound 11l significantly attenuated learning and memory impairment in an AD mouse model. Finally, a pharmacokinetic characterization of 11l indicated favorable druggability and pharmacokinetic properties. Taken together, our results suggest that 11l is a potential candidate for AD treatment and merits further investigation.

项与 H3 receptor 相关的新闻（医药）

2024-10-23

·Endpoints

Alto Neuroscience's mid-stage trial misses primary endpoint in depression

Alto Neuroscience’s stock tumbled 60% on Wednesday morning, the day after the company said a mid-stage trial for its oral small molecule failed to improve symptoms of major depressive disorder. In the Phase 2b trial, which the company described as a first-of-its-kind precision biomarker-based study in psychiatry, ALTO-100 didn’t show improvement over placebo in a change from baseline using the Montgomery-Åsberg Depression Rating Scale (MADRS) in 301 patients at the end of the six-week treatment period. The trial also didn’t hit “key” secondary endpoints that included efficacy versus placebo in MDD as measured using the Clinician Global Impression Scale-severity — a tool used to measure the severity of illness — and remission rates based on MADRS. Alto said the safety and tolerability profile was “favorable” and consistent with previous data. In a Phase 2a study last year, ALTO-100 hit the primary endpoint, with the treatment showing a greater improvement in both the monotherapy and adjunctive treatment groups. “We will move quickly to evaluate the full data set to better understand these findings and incorporate learnings from this large data set across our platform,” Alto CEO Amit Etkin said in a statement , adding that the company expects “our strong cash balance to support us through multiple near-term clinical milestones across our pipeline.” Alto $ANRO went public earlier this year, bringing in $129 million in February, above its original plans to raise $89 million. In its latest financial filing in August, the Eli Lilly-backed startup said it expects its existing cash to provide runway into 2027. ALTO-100 is still being investigated as an adjunctive treatment in a Phase 2b study in bipolar depression. Alto also has several upcoming data readouts for other assets that are expected next year. This includes ALTO-203, an H3 receptor inverse agonist, and ALTO-300 — both in major depressive disorder. In a note on Wednesday, TD Cowen analysts said they were disappointed by the newest slate of data but still “optimistic” about the drug. “We suspect the enrichment signal may have been seen in the adjunct MDD population,” TD Cowen’s Ritu Baral wrote. “Without additional detail on the Ph2b data, we hesitate to extend read-through to the rest of ANRO’s pipeline of agents paired with distinct biomarkers.” Others on Wall Street were more concerned. Jefferies analysts told investors they think the “study’s failure is driven by a lack of drug effect rather than [management] execution error” and that Tuesday’s data “raises questions around ANRO’s overall biomarker approach to CNS/psychiatry.”

临床2期临床结果临床失败

2024-10-04

·生物探索

Nat Commun｜龚为民/孙金鹏团队合作揭示整个组胺受体家族的配体识别及激活的分子机制

引言组胺是一种广泛分布的生物胺，是中枢神经系统中的神经递质，也是免疫系统、肠道和皮肤中的重要信号分子。组胺在人体中广泛存在，由肥大细胞、肠嗜铬样细胞和神经元等细胞分泌，参与一系列重要生理过程的调节，包括过敏反应、胃酸分泌、觉醒和炎症反应等。许多组胺功能由 G 蛋白偶联组胺受体介导，其中包括四个成员，H1R、H2R、H3R 和 H4R。事实上，长期以来人们一直认为组胺释放引起的炎症反应是由组胺 H1 受体介导的，而 H1 受体拮抗剂（通常称为抗组胺药）多年来一直用于治疗过敏。常用的组胺H1受体拮抗剂，如苯海拉明、异丙嗪、氯苯那敏等，是目前应用最广泛的非特异性抗过敏药物。此外，H2受体拮抗剂，如西咪替丁、尼扎替丁、雷尼替丁等，被广泛用于抑制胃酸过度分泌，治疗十二指肠溃疡、胃溃疡、胃食管反流、胃灼热等消化性溃疡病。此外，H3R拮抗剂匹特里赞特（Waxx®）已获批用于治疗发作性睡病和阻塞性睡眠呼吸暂停（Ozawade®）。组胺受体激动剂的药物开发进展则相对滞后。H1R的激动剂在理论上有可能调节神经系统的认知、觉醒等功能，但在外周组织中有促炎作用，目前定位的困难使其难以作为相关疾病的药物进行开发。H2R的激动剂则被研究发现有可能用于急性髓性白血病的治疗。H3R集中分布于神经系统，其激动剂不会在外周组织中引起副作用，因此很有潜力作为相关神经系统疾病如强迫性障碍的药物。H4R的激动剂也具有促炎作用，但用于疾病治疗的可能性有待于进一步研究。 2024年9月27日，中国科学技术大学龚为民课题组与山东大学孙金鹏课题组合作在Nature Communications杂志在线发表了题为Structural basis of ligand recognition and activation of the histamine receptor family的研究论文，系统报道了在内源性组胺或其他合成配体存在下，四种组胺家族受体亚型与四种不同的下游 G 蛋白复合的九种低温电子显微镜 (cryo-EM) 结构。该研究为理解所有四种组胺受体的配体识别和 G 蛋白偶联提供了一个结构框架，这可能有助于合理设计针对这些受体的配体。图组胺受体与相应 G 蛋白复合体的整体结构（Credit: Nature Communications）研究人员发现在组胺结合的H1R-Gq、H2R-Gs/q、H3R-Gi和H4R-Gi复合物中，酸性残基D3.32在组胺识别中起着关键作用，正如许多G蛋白偶联受体（GPCRs）在识别生物胺类分子时一样。同时，所有组胺受体的两个疏水残基Y/V3.33和Y6.51与组胺相互作用。D3.32-Y/V3.33-Y6.51基序在所有组胺受体中共享，表明该基序在组胺识别中起着关键作用。有趣的是，组胺在H3R和H4R的配体口袋中的结合方向与在H1R和H2R中的观察结果相反，这源于咪唑环旋转了约180°。进一步的结构和序列比较以及突变研究发现，H1R和H2R的TM6中保守的F6.52X2F6.55和H3R与H4R的TM7中的F7.39X3W7.43是决定这些不同结合方向的关键因素。结构比较显示，H1R和H2R的配体结合口袋与H3R和H4R的明显不同。H1R和H2R中存在两个特定口袋（正构口袋和次级结合口袋），而H3R和H4R中则存在三个特定口袋（正构口袋、次级结合口袋以及跨膜亚口袋）。这些口袋中的残基差异可以用于设计特异性靶向组胺受体成员的配体。此外，结构和药理学分析表明，immethridine （H3R选择性配体）刚性吡啶环与 H3R 中 L4017.42 的特异性相互作用是其对 H3R 而非 H4R 选择性的关键决定因素。H3R 中的 L4017.42 与 H4R 中的 Q3477.42 之间的序列差异也可以用于设计专门靶向 H3R 或 H4R 的配体。此外，研究人员发现在H2R胞质侧的ICL3是Gs/Gq耦合差异的决定因素。一个有趣的后续问题是，不同的组胺受体成员如何选择性地与Gs或Gi/Go蛋白耦合。研究人员通过更深入的结构和药理学分析发现，H2R的TM5与Gs更紧密的结合方式，以及H3R和H4R的R34.54-F/V6.25-R6.29基序与Gi/Go的独特相互作用，是不同组胺受体成员之间Gs和Gi/o选择性的基础。此项研究不仅可以进一步加深我们对整个组胺受体家族配体识别、激活及G蛋白耦合机制的理解，还可能有助于设计选择性靶向组胺受体家族成员的配体。参考文献 https://www.nature.com/articles/s41467-024-52585-y 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

2024-09-09

·GBIHealth

Y24H1财报速读：撤出中国！康乃德大幅转型，削减中国员工和业务，专注于美国市场

近日，多家药企陆续公布了2024年上半年财务业绩。康乃德上半年大幅转型，计划撤出中国市场而专注于美国区域。康乃德生物医药削减中国员工和业务康乃德生物医药（纳斯达克股票代码：CNTB）近日发布了2024年上半年财报，主要关注点包括其进一步撤出中国市场的计划。康乃德生物医药是一家中美生物技术公司，最初总部位于苏州，但后来迁至美国。根据该公司的新闻稿，康乃德生物医药正在转型成为一家专注于美国市场的公司，并正在采取积极措施大幅减少其在中国的业务。据报道，在过去的12个月里，该公司已经在中国裁撤了15%的员工，并计划在年底前进一步裁员。此外，该公司已经将主要候选药物 rademikibart的生产从中国转移至美国一家合同制造商，rademikibart是一款靶向 IL-4Rα 的全人源单抗，被誉为赛诺菲达必妥的最佳竞争者。2023年11月，康乃德生物医药将rademikibart在中国的开发、生产和商业化权利转让给了先声药业。其他降低成本的措施还包括将H3R拮抗剂的开发权利交还给许可方辉瑞。截至2024年6月，该公司拥有1.1亿美元的现金和等价物，足以维持运营到2027年。全球医疗情报领导者解锁隐藏在数据中的商业潜力关于 G B I ” 自从2002年成立以来，GBI始终以技术为驱动，为药企、器械及行业相关服务商提供贯穿生命周期的全球药品市场竞争数据、全球行业资讯、HCPs洞察、全国医疗器械数据等商业信息与洞察，助力企业在进行战略布局和决策时，脱颖而出。历经20余年的深耕细作GBI已成为95%以上跨国药企、国内头部药企、咨询与投资机构等医疗圈灯塔用户值得信赖的长期合作伙伴。联系我们投稿 | 发稿 | 媒体合作 ▶ zhangxinyue13@baidu.com 数据库 | 咨询服务 | 资讯追踪 ▶ 点击左下“阅读原文”完成表单填写点击阅读原文，解锁完整双语新闻

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